Human Dlk-1 (delta-like 1 homolog (Drosophila); which may be hereinafter referred to as “hDlk-1”) is a type I transmembrane (one-transmembrane-type) protein with a full length of 383 amino acid residues which has 6 EGF-like motifs in its extracellular region. The extracellular region shows homology with a Notch/Delta/Serrate family. A hDlk-1 gene has been cloned as a molecule expressed in a GRP (gastrin releasing peptide)-responsive lung small cell carcinoma-derived cell line (Non-Patent Document 1), or as a factor for suppressing preadipocyte differentiation (Non-Patent Document 2). From the viewpoint of the homology of the amino acid sequence of hDlk-1 with that of Delta that is a ligand of a Notch receptor as a cell differentiation regulator, such Dlk-1 is generally referred to as a gene symbol, DLK1. It also has several other gene symbols such as Pref-1 (Non-Patent Document 2), pG2 (Non-Patent Document 3), SCP-1 (Non-Patent Document 4) and ZOG (Non-Patent Document 5). However, these gene symbols basically indicate the same molecule.
Moreover, hDlk-1 is cleaved with an unidentified protease which cuts the neighborhood of cell membrane in the extracellular region of hDlk-1, and it is then secreted into blood. Free hDlk-1 (hDlk-1 extracellular region) is a molecule identical to a glycoprotein called FA-1 (Fetal antigen-1) (Non-Patent Document 6) consisting of 225 to 262 amino acid residues.
The hDlk-1 gene and a gene product thereof are expressed at a high level in undifferentiated, highly proliferative, fetal cells. In particular, the hDlk-1 gene and the gene product thereof are highly expressed in fetal liver, fetal kidney, fetal skeletal muscle, fetal brain and the like. After birth, however, expression of such a hDlk-1 gene and a gene product thereof can not be observed in most of the tissues. In normal adult tissues, the hDlk-1 gene and the gene product thereof are localized in adrenal gland, placenta and hypophysis (Patent Document 1, Non-Patent Document 2).
Furthermore, even in mature tissues, expression of hDlk-1 is observed in cells that are considered to be undifferentiated stem cells or precursor cells. For example, it has been reported that expression of hDlk-1 has been observed in hepatic oval cells that are undifferentiated and have pluripotency in adult liver (Non-Patent Documents 7 and 8) or in mesenchymal stem cells that are the stem cells of bone/cartilage/adipose cells (Non-Patent Document 9). It has been suggested that hDlk-1 is associated with the properties of such tissue stem cells, such as the maintenance of undifferentiation ability.
Such an expression pattern of hDlk-1 localized in fetal cells or stem cells and a family of genes/gene products having EGF-like motifs (Notch-receptor, Notch ligand (Delta, Jagged, serrate), etc.) generally controls the growth or differentiation of cells by intercellular interaction via EGF-like motifs. Thus, it has been suggested that hDlk-1 also has such functions. In fact, it has been well known that expression of hDlk-1 is decreased concomitant with differentiation of adipose precursor cells and that adipose differentiation is suppressed, if the hDlk-1 gene is forced to express in adipose precursor cells (Non-Patent Document 2). However, at the present time, details regarding a molecule (a ligand) interacting with hDlk-1 are unknown.
On the other hand, it has been reported that the hDlk-1 gene and the gene product thereof are expressed with a high frequency in various types of cancers or tumors. The types of cancers, in which expression of hDlk-1 has been confirmed so far, include: solid cancers such as neuroendocrine tumor, neuroblastoma, glioma, neurofibromatosis type 1, small cell lung cancer, liver cancer, kidney cancer and ovarian cancer (Patent Documents 1 and 2 and Non-Patent Documents 1, 3, 10, 11, 12, 13 and 14); and blood cancers such as myelodysplastic syndrome (Patent Document 3 and Non-Patent Documents 15 and 16) and acute myelocytic leukemia (Non-Patent Document 16). It has been reported that cell growth is accelerated if a hDlk-1 gene is introduced into a K562 cell that is an erythroleukemia cell line (Non-Patent Document 16) and also that, if such a hDlk-1 gene is introduced into glioblastomas, it causes the disappearance of contact inhibition of cells as well as acceleration of cell growth, so that anchorage-independent cell growth ability can be achieved. The relationship between hDlk-1 and carcinogenesis has been suggested (Non-Patent Document 17).
<Patent Documents>
    Patent Document 1: WO 2005/052156    Patent Document 2: WO 02/081625    Patent Document 3: Japanese Patent Laid-Open No. 2001-269174<Non-Patent Documents>    Non-Patent Document 1: Laborda, J. et al., J. Biol. Chem., vol. 268 (6), pp. 3817-3820 (1993)    Non-Patent Document 2: Smas, C. M. et al., Cell, vol. 73 (4), pp. 725-734 (1993)    Non-Patent Document 3: Helman, L. J. et al., Proc. Natl. Acad. Sci. USA, vol. 84, pp. 2336-2339 (1987)    Non-Patent Document 4: Maruyama, K. et al., Unpublished, Genebank accession number D16847 (1993)    Non-Patent Document 5: Halder, S. K. et al., Endocrinology, vol. 139, pp. 3316-3328 (1998)    Non-Patent Document 6: Fay, T. N. et al., Eur. J. Obstet. Gynecol. Reprod. Biol., vol. 29, pp. 73-85 (1988)    Non-Patent Document 7: Tanimizu, N. et al., Gene Expression Patterns, vol. 5, pp. 209-218 (2004)    Non-Patent Document 8: Jensen, C H. et al., Am. J. Pathol., vol. 164 (4), pp. 1347-1359 (2004)    Non-Patent Document 9: Abdallah, B. M. et al., J. Bone Miner. Res., vol. 19 (5), pp. 841-852 (2004)    Non-Patent Document 10: Jensen, C. H. et al., Br. J. Dermatol., vol. 140 (6), pp. 1054-1059 (1999)    Non-Patent Document 11: Jensen, C. H. et al., Tumour Biol., vol. 20 (5), pp. 256-262 (1999)    Non-Patent Document 12: Yin, D. et al., Int. J. Oncol., vol. 24 (4), pp. 1011-1015 (2004)    Non-Patent Document 13: Yin, D. et al., Oncogene, vol. 25 (13), pp. 1852-1861 (2006)    Non-Patent Document 14: Fukuzawa, R. et al., J. Clin. Pathol., vol. 58, pp. 145-150 (2006)    Non-Patent Document 15: Miyazato, A. et al., Blood, vol. 98, pp. 422-427 (2001)    Non-Patent Document 16: Sakajiri, S. et al., Leukemia, vol. 19 (8), pp. 1404-1410 (2005)    Non-Patent Document 17: Yin, D. et al., Oncogene, vol. 25 (13), pp. 1852-1861 (2006)